The compound (±)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine, also referred to as (±)-5-[α-(2-dimethylaminoethoxy)benzyl]-1-methyl-1H-pyrazole, or Cizolirtine, of the formula was described in European Patent EP 289 380. This compound is a potent analgesic which is currently in phase II clinical trials. Optical resolution by fractional crystallization with optically active acids has been applied to the Cizolirtine racemate (as described in International Publication WO 99/02500).
A further family of active compounds wherein a thiophene ring is present instead of the phenyl ring has been described in International Publication WO 99/52525. Among them, the compound (±)-2-[thienyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine of formula (I) is currently in clinical trials for the treatment of depression. It can be prepared by O-alkylation of the compound of formula II: 
The carbinols such as the one of formula II are key intermediates to reach the compounds described in International Publication WO 99/52525. The pure enantiomers of (+)-I and (−)-I may be prepared by separately O-alkylating the enantiomerically pure intermediates (+)-II and (−)-II. Thus, a synthetic process to the enantiomerically pure/enriched intermediates (+)-II and (−)-II is needed.
The enantioselective reduction of prochiral ketones has been proposed in organic synthesis to obtain secondary alcohols with high enantiomeric purity. Accordingly, a number of strategies for the asymmetric reduction of prochiral ketones to single enantiomer alcohols have been developed [R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed., 2001, 40, 40–73].
A strategy for the enantioselective reduction of aromatic and heteroaromatic prochiral ketones with high ee values includes the use of an optically active diphosphane/Ru/diamine/inorganic base catalyst system. Examples of asymmetric reduction of heteroaromatic ketones are disclosed in International Patent Publication WO 2004/011452 and in P. Cao, X. Zhang, J. Org. Chem. 1999, 64, 2127. Enantioselective hydrogenation of ketonic structures to nonracemic secondary alcohols has also been achieved with a wide range of chiral ruthenium catalyst systems, which can be prepared by different combinations of Ru (II) chiral phosphanes and diamine ligands. The extent of the enantioselectivity obtained with the different ketones depends largely on the nature of the substituents of the prochiral ketone, as shown by the state of the art [see, for instance, Table 2, on p. 53: R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed. 2001, 40, 40–73]. It is also known that heteroaromatic ketones can be enantioselectively hydrogenated to nonracemic secondary alcohols with these chiral ruthenium catalysts systems [C. Chen, R. A. Reamer, J. R. Chilenski, C. J. McWilliams, Org. Lett. 2003 5, 5039].
Nonetheless, it has been found that one specific catalyst or a class of catalysts cannot be used equally well in all hydrogenations. Thus, to attain satisfactory ee values by the enantioselective hydrogenation of prochiral ketones, each hydrogenation problem has to be investigated separately with regard to the substrate, the catalyst and the reaction conditions for finding the optimal conditions to obtain the best results.